Green Chemistry Highlights
pubs.acs.org/OPRD
The Green Chemistry Articles of Interest
1. INTRODUCTION
The American Chemical Society’s (ACS) Green Chemistry
Institute (GCI) Pharmaceutical Roundtable (PR) was developed
in 2005 to encourage the integration of green chemistry and
green engineering into the pharmaceutical industry.
The Roundtable currently has 16 member companies as
compared to three in 2005. The membership scope has also
broadened to include contract research/manufacturing organ-
izations, generic pharmaceuticals, and related companies.
Members currently include ACS GCI, Amgen, AstraZeneca,
Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Dr.
Reddy’s, DSM Pharmaceutical Products, Eli Lilly and Company,
GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc.,
Novartis, Pfizer, Inc., Roche, and Sanofi.
One of the strategic priorities of the Roundtable is to inform
and influence the research agenda. Two of the first steps to
achieve this objective were to publish a paper outlining key green
chemistry research areas from a pharmaceutical perspective
(Green. Chem. 2007, 9, 411−420) and to establish annual ACS
GCIPR research grants. This document follows on from the
Green Chemistry paper and is largely based on the key research
areas, though new sections have been added. The review period
covers April 2013−September 2013.
These articles of interest represent the opinions of the authors
and do not necessarily represent the views of the member
companies. Some articles are included because, whilst not
currently being regarded as green, the chemistry has the
potential to improve the current state of the art if developed
further. The inclusion of an article in this document does not
give any indication of safety or operability. Anyone wishing to
use any reaction or reagent must consult and follow their
internal chemical safety and hazard procedures.
2. SOLVENTS
A special issue of Current Organic Chemistry was dedicated to
green solvents in the synthesis of pharmaceuticals (Curr. Org.
Chem. 2013, 17, 1131). Next to articles on biocatalysis and
dynamic kinetic resolution, a review paper on green solvents in
organic synthesis is included, covering several main classes of
environmentally benign solvents, namely water, fluorous solvents,
ionic liquids, organic carbonates, scCO2, and biosolvents. The
focus of the article is on new evolutions in the last 15 years and
on the complementarity of these alternatives (Curr. Org. Chem.
2013, 17, 1179−1187).
Liu et al. published a communication on catalysts and
additive-free synthesis of disulfides in the biobased green
solvent ethyl lactate. This solvent was compared to traditional
solvents like DMF and toluene and showed an interesting
promotion effect of ethyl lactate on this thiol-coupling reaction
(RSC Adv. 2013, 3, 21369−21372).
Sutter et al. evaluated the toxicological profile of the glycerol-
based 1,2,3-trimethoxypropane. It is proposed by the authors
to be an alternative green solvent as it gives a negative result in
the Ames test, has low acute toxicity, relatively high flash-
point (45 °C), and low ecotoxicity in an aquatic environment.
© XXXX American Chemical Society
An application of this new solvent in hydride reduction reac-
tions is reported, and a specific new process for the reduction
of nitriles to amines in 2-MeTHF and in 1,2,3-TMP in using
1,1,3,3-tetramethyldisiloxane (TMDS) in combination with
copper triflate Cu(OTf)2 is developed and described (Green
Chem. 2013, 15, 3020−3026).
McGonagle et al. have published a solvent selection guide
for aldehyde-based direct reductive amination processes. A
SciFinder survey indicated that 25% of published reductive
aminations use either dichloromethane (DCM) or dichloroethane
(DCE) as solvent. In the study three commonly used reagents are
examined, sodium cyanoborohydride, sodium triacetoxyborohy-
dride (STAB), and picoline−borane complexes. The results for
reactions with DCM and DCE are compared with greener
solvents such as ethyl acetate, IPA, and certain ethers. The results
of the study show that chlorinated solvents are not required,
particularly when using STAB as the reducing agent (Green
Chem. 2013, 15, 1159−1165).
3. AMIDE FORMATION
Kang et al. have reported on the reaction of nitriles and alcohols
under ruthenium-catalyzed conditions to generate amides in a
redox-neutral single step with complete atom economy. The
reaction differentiates itself from previous amidation reactions
utilizing these components in that the carbon of the nitrile is not
the carbonyl source in the reaction, and instead the reaction
proceeds through hydrogen transfer from the alcohol to nitrile
with the subsequent C−N bond formation between the nitrogen
of the nitrile and the α-carbon of the primary alcohol. Screening
studies on a model system indicated that RuH2(CO)(PPh3)3
with an NHC precursor (1,3-diisopropylimidazolium bromide)
as ligand were the optimal catalyst system with toluene at reflux
as the solvent and sodium hydride added as base. A range of
both aliphatic and aromatic nitriles were successful substrates
with the main limitation being functional groups that were
unable to tolerate the basic reaction conditions. Similarly, good
substrate scope was observed with respect to the primary
alcohol employed. Given the relative ease of accessing isotope-
labelled nitriles, this methodology was demonstrated to be
effective for the synthesis of labelled-amides with complete
isotope incorporation. Deuterium labelling at the α-CH2 of the
alcohol demonstrated unequivocally that hydrogen generated
from alcohol oxidation is responsible for the reduction of the
nitrile, and NMR studies confirmed the involvement of imine
intermediates (J. Am. Chem. Soc. 2013, 135, 11704−11707).
Received: May 27, 2014
Accepted: June 5, 2014
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Organic Process Research & Development
Sun et al. have reported on the formation of amides from
aromatic amines utilizing 1,3-diketones as the acylating agent.
The reaction proceeds via a novel C−C bond cleavage under
oxidative metal-free conditions with water as the solvent. Initial
screening indicated 30% hydrogen peroxide to be the optimal
oxidant. Various anilines were successful substrates for the
reaction though those bearing electron-withdrawing substitu-
ents required elevated reaction temperatures. Aliphatic amines
failed to react under the reaction conditions. Various diketones
were also evaluated as acylating agents, and steric hindrance
was demonstrated to be a critical factor in the efficiency of the
acyl transfer. Control experiments to determine the mechanism
suggest that the reaction proceeds through an enamine
intermediate via a radical mechanism (Green Chem. 2013, 15,
3289−3294).
Lanigan et al. have published on the use of B(OCH2CF3)3 to
promote the reaction between carboxylic acids and amines
to generate the corresponding amides. An alternative scalable
synthesis of the reagent from B2O3 is described, and the
compound can be stored at room temperature under nitrogen
for ∼4 months without decomposition. In addition, a novel
work-up has been developed using a series of commercially
available scavenger resins to enable isolation of the pure amide
directly from the reaction mixture. The scope of the amida-
tion process is also evaluated. In examples with acids with
adjacent chiral centres, no significant racemization was involved,
and the protocol was extended to the formation of dipeptides.
B(OCH2CF3)3 was also demonstrated to be an effective reagent
for the formylation of both primary and secondary amines with
DMF (J. Org. Chem. 2013, 78, 4512−4523).
Das et al. have published on the use of nano magnesium
oxide (MgO) to promote the formation of amides under
solvent-free reaction conditions. The reactions took place at
70 °C with the catalyst being recovered by centrifugation, and
able to be recycled through 5 reactions without loss of activity.
The optimum catalyst load was 5 mol %, with a loss of activity
noted at higher loadings, which is believed to be due to a
decrease in surface area due to particle aggregation. The catalyst
was characterized by numerous techniques such as EDX, FTIR
and SEM micrographs, and changes observed as the catalyst
lost activity. The activity of the catalyst system is attributed
to its enhanced basicity, and this is correlated against yield over
a range of catalyst loadings. Numerous carboxylic acids and
amines are reported to couple in good to excellent yields under
the optimized conditions, though aliphatic dicarboxylic and
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Green Chemistry Highlights
long-chain monocarboxylic acids are not good substrates. A
plausible mechanism is provided in which the nano-MgO activates
the carboxylic acid on its surface throughout the amide bond
formation (Appl. Catal., A 2013, 456, 118−125).
Two groups have published on the oxidative amidation of
benzylic alcohols catalyzed by iron salts in the presence of an
oxidant. Gaspa et al. have utilized FeCl3·6H2O with 70%
aqueous TBHP as the oxidant. Initially the amine is reacted
with NCS to generate the N-chloroamine in situ, which can
then be consecutively treated with the alcohol, catalyst, and
oxidant. Electronic or steric effects on the aromatic ring of the
benzylic alcohol were shown to have little influence on the
reaction, and both primary and secondary amines were well
tolerated. A radical-type mechanism is proposed (Org. Biomol.
Chem. 2013, 11, 3803−3807). The system of Ghosh et al.
utilizes Fe(NO3)3·9H2O as the catalyst, and the reaction
proceeds in a tandem fashion. Initially, the alcohol is oxidized in
the presence of catalytic amounts of the iron salt and TEMPO
with air as the stoichiometric oxidant. After 2 h, the amine
hydrochloride salt, calcium carbonate, and 70% aqueous TBHP
are added, and the reaction is heated to 60 °C for 16 h to form
the amide. Again, a range of primary and secondary amines
were well tolerated, and little effect was noted based on the
electronic properties of the benzylic alcohol. In the case of
chiral amine salts, no racemization was detected during the
amidation, and again a radical-type mechanism is proposed
(Tetrahedron Lett. 2013, 54, 4922−4925).
4. OXIDATIONS
C−H functionalization is an important area for green chemistry
since it offers opportunities for shorter synthetic routes with
reduced waste. Roduner et al. reviewed recent advances in
C−H oxidations using molecular oxygen, covering both organo-
metallic and biocatalytic approaches. The authors address a critical
aspect of reactions using oxygen that is not often addressed in
publications: safety. Two ways of safely using oxygen are
reviewed, including supercritical CO2 and water as solvents, and
flow chemistry in microreactors (ChemCatChem 2013, 5,
82−112).
Use of biocatalysis for oxidations is an area of growing
interest and application in the pharmaceutical industry. The
Turner group at Manchester pioneered the use of engineered
monoamine oxidases (MAO) for the preparation of chiral amines.
The latest paper from this group describes the development
of a number of variants of MAOs derived from Aspergillus niger
Organic Process Research & Development Green Chemistry Highlights

having broad substrate scope and applications in deracemization
reactions of substrates of pharmaceutical interest. The deracem-
ization process consists of a cycle in which an MAO selectively
oxidizes one enantiomer of a racemic amine to an imine, with
BH3−NH3 converting the resulting imine back to the racemic
amine. Repeated cycles thus provide a single enantiomer of the
amine with high yield and ee.
in water at 100 °C, a reaction that produces only water and
t-BuOH as waste. The reaction is tolerant of a number of func-
tional groups and also is effective with substrates containing
pyridines and thiophenes. The authors propose a mechanism in
which the alcohol is first oxidized to the aldehyde, which then
forms a hemiaminal with ammonia, followed by oxidation to
the primary amide. The drug piracetam was prepared using this
methodology as the final step in the synthesis (Green Chem.
2013, 15, 1956−1961).

Particularly noteworthy was the application of this method-

ology to the synthesis of (R)-harmicine using the oxidase
enzyme for two transformations. First, an indole intermediate
is nonselectively oxidized to an iminium ion which is trapped
by the nucleophilic indole to afford racemic harmicine. Next,
deracemization in the same reaction vessel via the oxidation/
reduction sequence using borane−ammonia produces (R)-
harmicine in overall 83% yield and >99% ee (J. Am. Chem. Soc. Elimination of highly toxic metals is a goal of green chemistry.
2013, 135, 10863−10869). However, when these metals are required for a particular
transformation, immobilization is an excellent way to minimize
exposure and permit reuse. Basavaraju et al. report the immobili-
zation of OsO4 by construction of a flow reactor with the
wall surface modified with a nanobrush polymer coating of
poly(4-vinylpyridine) used to immobilize OsO4 via ligation to
the pyridine units (Angew. Chem. 2013, 52, 6735−6738).

5. ASYMMETRIC HYDROGENATIONS
Liu et al. have developed an enantioselective metal-free hydro-
genation of imines by using simple chiral boranes as catalyst.
The active catalyst was generated in situ from hydroboration of
chiral dienes with HB(C6F5)2, thus allowing a wide range
Base metal catalysis is an area of renewed interest given the of catalysts to be evaluated. Once an optimal catalyst structure
inherent lack of sustainability for processes based on precious was identified, temperature and solvent effects were evaluated.
metals. Iron is a preferred metal catalyst, not only due to its Temperatures between 30 and 0 °C had little impact on enantio-
abundance but also for its low toxicity. Regarding oxidants, selectivity. Solvent effects were pronounced, and mesitylene was
H2O2 is a preferred green oxidant since the only waste identified as optimum. Using optimized conditions of 2.5 mol %
produced is water. Lenze and Bauer combine both these green diene and 5 mol % HB(C6F5)2 in mesitylene at 25 °C, a variety
aspects for the oxidation of 1,2-diols catalyzed by iron(II) of biaryl substituted imines were screened. Substitution was
complexes using H2O2 in MeCN, finding that the secondary limited primarily to the carbon-bound aryl group, and altera-
alcohol is selectively oxidized vs the primary alcohol. Five amine tion of the methyl group of the imine had little effect on
ligands were studied, with the symmetrical bis-pyridyl amine (1)
as the most effective. The authors conducted preliminary studies
to delineate the mechanism but did not draw firm conclusions.
Regardless of whether the reaction proceeds via hydride- or
hydrogen-atom abstraction, or via electron transfer, the stability
of the incipient secondary α-hydroxy carbon radical, cation, or
radical cation, over the primary species is likely to be responsible
for the observed selectivity. It is also worth noting that the
1,2-diol substrates do not suffer from C−C bond cleavage which
is the most common outcome with the majority of strong
oxidizing agents (Chem Commun. 2013, 49, 5889−5891).

Continuing with the theme of alcohol oxidations, Wu et al.

report a metal-free oxidation of primary and benzylic alcohols
to primary amides using tert-butylhydroperoxide and ammonia
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Organic Process Research & Development
enantioselectivity. Under mild reaction conditions asymmetric
reduction is achieved up to 99% yield and 89% ee (J. Am. Chem.
Soc. 2013, 135, 6810−6813).
Continuous flow technology is considered to be one of
the best alternatives to batch mode operations in R&D and
manufacturing. Duque et al. have developed a continuous-flow,
solvent-free asymmetric hydrogenation strategy to reduce dibutyl
itaconate to (S)-dibutyl 2-methylsuccinate at room temperature
under 5 bar H2 pressure in the presence of Rh−MeDuPHOS
catalyst immobilized on alumina using phosphotungstic acid
as the anchor. The conversion and enantioselectivity were found
to be up to 99% and 98%, respectively. The low operating
pressure utilized in this protocol allows for a more efficient use
of hydrogen, and the product can be accessed without decom-
pression. Leaching of Rh is very low, allowing for extended run
times; however, the ee began to decrease after 23 h, and
conversion began to decrease after 47 h continuous reaction time
(Angew. Chem. Int. Ed. 2013, 52, 9805−9807).
Ru/SNNS [N,N-bis(2-tert-butylthiobenzylidene)-1,3-
propanediamine] systems are analogous to chiral PNNP and
salen Ru complexes and are found to have potential similar to
that of Ru diphosphine complexes. This is the first catalyst of its
kind that has been tested for asymmetric hydrogenation of
simple to hindered/unsaturated ketones in high yields (98%)
and enantioselectivity (95% ee). The substrate/base/catalyst
ratio was found to be in the order of 2000/100/1; in some
cases it was as high as 29300/1083/1. This system has better
features as it can tolerate air and moisture. Catalysts based on
Ru/SNNS show excellent chemoselectivity in the reduction of
unsaturated ketones and aldehydes with S/C ratios up to 106/1.
In situ formation of the catalyst without base was also found to
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Green Chemistry Highlights
be effective, although with inferior yields and enantioselectivities
(Angew. Chem. Int. Ed. 2013, 52, 1−5).
An Ir(I)phosphine−phosphite complex has been developed
and employed in the asymmetric reduction of various imine
hetereocyles, i.e. benzoxazines, benzoxazinones, benzothiazinones,
and quinaxalinones for the first time. The catalyst loading was
found to be in the order of 0.5−2 mol %. This catalytic system
works at room temperature and affords the product in excellent
yields (94−99%) and enantioselectivities (94−99% ee). Mecha-
nistically, stepwise proton and hydride transfers are thought to
be the favored pathways to afford products (Org. Lett. 2013, 15,
2066−2069).
The potential of BIPI (phosphinoimidazole) ligands in com-
bination with Ir(cod)BArF have been exploited in the asymmetric
reduction of difficult substrates, i.e. dimethylindene and
dimethyldihydronaphthalene. Screening identified ligand 2, having
the fluoride substituent, as extremely effective. A brief screen of
solvents was conducted, and dichloromethane gave higher conver-
sion compared to methanol or toluene. Various tetrasubstituted
olefin substrates have been tested, and the conversion and enantio-
selectivities of these were found to be excellent under optimized
conditions, consisting of 2 mol % catalyst, in dichloromethane at
0 °C (Adv. Synth. Catal. 2013, 355, 1455−1463).
6. C−H ACTIVATION
Huang et al. have developed an iron-catalyzed oxidative radical
cross-coupling/cyclization to synthesize dihydrobenzofurans.
A combination of 10 mol % FeCl3 and 1.2 equiv DDQ are used to
couple electron-rich phenols and napthols with styrene or styrene
derivatives. The reaction is initiated through DDQ-promoted one-
electron phenol oxidation. Iron coordination of the oxidized
phenol stabilizes the carbon−centred radical which then under-
goes addition with styrene followed by C−O bond formation.
While the chemistry is quite mild and uses iron as a green catalyst,
one drawback is that 2 equiv of olefin are required to obtain high
yields (Angew. Chem. Int. Ed. 2013, 52, 7171−7155).
Organic Process Research & Development
A C−H lactonization method has been developed which
efficiently constructs biaryl lactones via carboxylic acid-directed
C−H functionalization/C−O bond reductive elimination. The
reaction uses a simple catalyst system, 5 mol % Pd(OAc)2 and
15 mol % N-acetylated glycine, for C−H functionalization of
2-aryl carboxylic acids. The terminal oxidant is (diacetoxyiodo)-
benzene which is believed to generate a palladium(IV) inter-
mediate that can more readily undergo C−O reductive elimination.
The reaction scope is broad; however, ortho-substituted biaryl
acids couple in moderate yields (∼50%) with >30% recovered
starting material. The authors demonstrate the utility of the
method through the synthesis of cannabinol which requires two
successive C−H lactonization steps (Org. Lett. 2013, 15,
2574−2577).
Pirnot et al. have developed a method for direct activation at
the β-position to a carbonyl via photoredox activation. The
system they optimized takes advantage of a common household
compact fluorescent bulb and a commercially available catalyst
with only 1 mol % loading. An amine cocatalyst facilitates
enamine formation with the aldehyde, followed by enamine
oxidation and the subsequent nucleophilic radical coupling
with the arene at the β-position. Good yields from 44−86% for
a variety of aldehydes and ketones in a cyclic 6-membered
ring system when X = C and EWG = CN are reported. Also,
a variety of electron-withdrawing groups including pyridine
systems where X = N delivers good yields, with the best yields
provided by esters and sulfones at the ortho and para positions.
The real highlight of this methodology may be the ability to use
a cinchona-based amine catalyst to deliver chiral products. At
this time they only highlight one example with cyclohexanone
delivering 50% ee, but studies are ongoing. The authors do
highlight the unfortunate formation of an equivalent of cyanide
during the course of the reaction, generating an aqueous waste
stream which must be treated accordingly. Finally, another draw-
back to consider is reaction time, with most reactions requiring
times in the 48 h range (Science. 2013, 339, 1593−1596).
In another example of photocatylzed C−H activation, Yoon
and co-workers have developed a Brønsted acid-cocatalyzed
radical photocatalytic C−H activation at the α-amino site
of tertrahydroisoquinolines. First, conditions were optimized
with the use of a 23 W compact fluorescent lamp and the
commercially available Ru(bpy)3Cl2 catalyst. During the course
of investigations to improve the reaction rate by increasing the
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Green Chemistry Highlights
ionic strength of the reaction, a pH-dependent Brønsted acid-
cocatalyzed reaction was discovered where 1 equiv of TFA
provided the best yield. These conditions decrease reaction
time significantly to 5 h (23 without TFA) and improve yield to
90% (60% without TFA). Substitution on the amine−phenyl
ring was well tolerated as well as on the aromatic positions of
the tetrahydroisoquinoline. A small sampling of other Michael
acceptors also resulted in good yields. The authors present a
significant amount of detail into the mechanistic understanding
of the reaction and studies to optimize the pH for this process,
highlighting the benefit this genre of Brønsted acid-cocatalyzed
reaction systems may have on other radical processes (J. Org.
Chem. 2013, 78, 4107−4114).
7. GREENER FLUORINATION
Mazzotti et al. reported a robust, scalable, and practical
palladium-catalyzed fluorination of arylboronic acids. Prior to
this work, the catalytic alternatives providing such function-
alized aryl fluorides consisted of Pd-catalyzed fluorination of
aryl triflates, or the silver-catalyzed fluorination of stannanes.
The current work constitutes an obvious improvement from an
environmental standpoint. The Pd-catalyzed fluorination
uses terpyridyl Pd (II) complex as a precatalyst. It proceeds
in DMF or acetonitrile and converts aryl trifluoroborates, or
even their boronate esters or boronic acids, both electron−rich
and poor, into their corresponding fluorides. The methodology
is compatible with a wide range of functional groups (ketones,
amides, carboxylic acids, esters, bromides, heterocycles) and
results in yields ranging from 63% to 99%. The paper comprises
useful mechanistic considerations which should further help in
optimization specific to a substrate in the future (J. Am. Chem.
Soc. 2013, 135, 14012−14015).
Bloom et al. reported an elegant iron-catalyzed benzylic
fluorination method as a synthetic equivalent to 1,4-conjugate
addition of fluoride. Iron(II) acetylacetonate was demonstrated
to catalyze effectively the net conjugate fluorination formally
carried out with Selectfluor. While a large excess of fluoride
source is still being used, the ability to derivatize an activated
but unfunctionalized benzylic position offers an interesting
alternative in terms of feedstock. In addition, it enlarges the
scope and utility of iron as a catalyst. The methodology was
demonstrated on a wide range of aromatics and proceeded in
modest yields (38% to 75%) with improved reactivity on esters
and carboxylic acids. Although still suffering from modest yields,
the mild conditions combined with an operationally simple and
robust process makes this chemoselective transformation highly
Organic Process Research & Development Green Chemistry Highlights

attractive, and prone to future development (J. Org. Chem. 2013,

78, 11082−11086).

Terpenoid products obtained from the cyclisation of a

8. BIOCATALYSIS polyisoprene backbone have important applications from chiral
Many enzyme-catalysed reactions such as ketoreduction, building blocks in synthesis to therapeutic compounds such as
transamination, and monooxygenation are showing increasing taxol and artemisinin. Seitz et al. demonstrated that triterpene
use in chemical synthesis. Whilst the development of naturally cyclases can be used to generate di- and triheterocycles from
occurring reaction types is continuing, it is not necessary to functionalized, shortened polyisoprene units. This highlights
limit biocatalysis to reactions which have natural precedents. the versatility and flexibility of these enzymes to act as general
Coelho et al. demonstrated this concept by altering the activity Brønsted acid catalysts. Using a cyclase from Zymomonas mobilis,
of cytochrome P450BM3 from Bacillus megaterium from oxygena- a range of terminal nucleophiles could be used to produce
tion to cyclopropanation. By substituting a cysteine thiolate cyclic ethers, enol ethers, and lactones in reasonable yields
ligand with a weakly donating serine, the authors raised the (ChemBioChem 2013, 14, 436−439).
FeIII/II potential and allowed the enzyme to facilitate an
NAD(P)H-driven reaction. This mutation also removed mono-
oxygenation activity from the protein. The engineered enzyme
was shown to work in vivo for the cyclopropanation of styrene
under anaerobic conditions. Despite the use of ethyldiazoacetate
which is a drawback, the product was formed in good yield and
with high diastereo- and enantioselectivity (Nat. Chem. Biol.
2013, 9, 485−487).

Conducting more than one reaction in the same vessel can

To further expand the transformations catalysed by the
engineered P450BM3 enzyme, McIntosh et al. reported an intra-
molecular C−H amination. Using E. coli cells in vivo under
anaerobic conditions, high yields, total turnover numbers (TTN),
and ee could be achieved. These results compare favorably with
those previously reported for this transformation by chemical
methods (Angew. Chem. Int. Ed. 2013, 52, 9309−9312).
make processes much more sustainable as it can reduce cycle
times and energy consumption, as well as minimise both yield
loss and waste. Enzymatic processes in particular have great
potential for one-pot cascades as reaction conditions tend to be
more similar than for chemical reactions. Liu and Li have
shown this approach is possible for the synthesis of (R)-2-alkyl-
δ-lactones from 2-alkylidenecyclopentanones. This system uses
an enoate reductase from Acinetobacter sp. RS1 and a Baeyer−
Villiger mono-oxygenase expressed in E. coli. The whole cells
expressing each enzyme are added sequentially to a single pot,
and the product lactones are produced in good yields and high
enantioselectivity (ACS Catal. 2013, 3, 908−911).

One of the more aspirational transformations in the ACS

Green Chemistry Institute Pharmaceutical Roundtable’s 2007
paper was the asymmetric hydrogentation of unfunctionalized
olefins, enamines, and imines. The reduction of this last class of
substrates has recently been reported by Rodriguez-Mata et al.
Using an (R)-selective imine reductase (IRED), Q1E1E0 from
Streptomyces kanamyceticus, 2-methyl-1-pyrroline could be
reduced to (R)-2-methylpyrrolidine in low yield but excellent ee.
Moreover, the crystal structure of the protein was solved, and
it is hoped that this may help deduce the mechanism of this
reaction and provide a basis for rational engineering of the Interestingly, the ee of the product is higher than that
enzyme (ChemBioChem 2013, 14, 1372−1379). observed in the initial reduction reaction, indicating possible
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degradation of the product lactone. It was found that hydrolysis

of the (S)-2-alkyl-δ-lactone was being catalysed by Acinetobacter
sp. RS1, causing the ee of the (R)-δ-lactone to be upgraded.
As more and more novel biocatalysts and enzyme-catalysed
reactions are discovered, this brings into focus the need to
think differently about the way molecules could be constructed.
To assist in this regard, Turner and O’Reilly have proposed
that new guidelines for “biocatalytic retrosynthesis” should be
developed for future training and education of synthetic chemists
(Nat. Chem. Biol. 2013, 9, 285−288). substrate to generate a relatively stable tertiary cation. In the
absence of Et2O, dimerization of the substrate occurs (Angew.
9. REDUCTIONS Chem., Int. Ed. 2013, 52, 7492−7495).
It has long been known that hot, alkaline conditions decompose
sugars to hydrogen and a variety of low-molecular weight organic
species, e.g. lactate, formate, and acetate. Kumar et al. have
exploited this and used D-glucose as the sole reducing agent in a
catalyst-free process. There are some deficiencies in the system at
the present time. There is a requirement for an extended hold
at elevated temperatures, but at present, substrate concentra-
tions are only 0.25 M, and there is clear scope for optimisation. One crucial aspect to be considered for industrial application
Nonetheless, impressive chemoselectivity was reported with of FLPs (and indeed other novel research technologies) is the
halide, vinyl, carbonyl, and even additional nitro substituents tolerance towards impurities. Cost concerns typically mean that
remaining unaffected by the conditions. Yields were in the range solvents and other reagents are used at lower specification than
47−99% across a total of 22 substrates (RSC Adv. 2013, 3, in a research environment where prepurification is common. In
4894−4898). the FLP-catalyzed hydrogenation of imines, residual amounts of
aldehyde and water can lead to catalyst poisoning. Thompson
et al. have explored the use of scavengers with common FLP
systems and shown that small amounts of tri-isobutylaluminum
(TIBAL) or triethylsilane can prevent poisoning and can even
restore activity in a stalled reaction. Seven substrates were con-
sidered in this work, although chemoselectivity was not broadly
investigated apart from the presence of aryl halides. One aspect
of this work is that typical catalyst loadings are already around
0.5−2.5 mol % with the potential to reduce further although
loadings are higher for some electron-rich systems (Org. Process
Possibly the most studied of the metal−free reducing agents Res. Dev. 2013, 17, 1287−1292).
are the frustrated Lewis pairs (FLP). These systems deliver
both hydrogen activation and subsequent reduction of organic
compounds via noninteracting Lewis acid/base centres. A com-
mon component in such systems is tris(pentafluorophenyl)-
borane. Now Nicasio et al. have shown that related boranes
showing reduced Lewis acidity can also function effectively in
the reduction of electron-deficient olefins. They determined
that the rate-limiting step in such reductions was the transfer
of hydride from an intermediate borohydride species [e.g.,
(F5Ph)3BH−]. Moderating the Lewis acidity of the borane
species facilitated subsequent hydride transfer while still The above FLP cases might be viewed as niche examples that
allowing heterolytic hydrogen cleavage. Control experiments require lengthy reaction times and whose green credentials are
showed that both components were necessary for reaction to limited to avoiding the use of endangered metals. As the field
occur, applying the isolated borohydride reagent followed by develops, however, the scope for optimising Lewis acid/base
a DABCO·H+ quench was not successful. Optimal conditions partners and additives will increase and limitations of substrate
were reached using (2,4,6-F3Ph)3B as Lewis acid. A range of range and catalyst activity will reduce. We are beginning to see
substrates could be reduced using this system where the olefin that these approaches do show the potential for more tailored
was activated by ester, sulfonyl, and nitro groups. However, systems to be developed that offer scope for competitive metal-
apart from the nitroolefins, it was necessary for >1 electron- free reductions.
withdrawing group to be present (RSC Adv. 2013, 3, Base metal catalysis has gained in popularity as an alternative
21369−21372. Chem. Eur. J., 2013, 19, 11016−11020). to the use of precious metal catalysts. Typically having lower
Generally FLP systems utilize a P- or N-centred Lewis base, toxicity and greater abundance, this strategy is a green approach
Hounjet et al. have now shown that even simple ethers can to catalytic methodologies. Four papers that demonstrate the
function as promoters in certain situations and have demon- power of this strategy using iron catalysts were published during
strated the hydrogenation of 1,1-diphenylethylene with >95% the current review period. One strategy using in situ formed iron
conversion. It appears that the critical aspects of this approach heterocyclic carbene complexes was reported by Volkov et al.
are the Lewis basicity of the ether and the ability of the Using N,N-dimethylbenzamide as a model substrate, conditions
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Organic Process Research & Development
were refined that produced both high activity and selectivity
for the amine, versus formation of the aldehyde and alcohol
products. Iron(II) acetate and the ionic liquid [Ph-HEMIM]-
[OTf] were used under further refinement of silane and solvent.
Using these results, a mechanism was proposed that led to the
final optimized conditions. The reduction was reported with aryl
or heteroaryl tertiary amides, using 1 mol % iron(II) acetate,
1.1 mol % [Ph-HEMIM][OTf], 2.2 mol % n-BuLi, 1 mol %
LiCl, and 3 equiv polymethylhydrosiloxane (PMHS) in THF at
65 °C, affording the tertiary amine product in high yield with
relatively short reaction time. Reactions using primary or
secondary amides failed to produce product (Eur. J. Org. Chem.
2013, 2066−2070).
Selective reduction of conjugated α,β-unsaturated aldehydes
to provide allylic alcohols is a challenging problem in chemical
synthesis. Wienhöfer et al. published a paper using iron catalysis
to address this. Extending the use of an iron complex previously
identified by the Beller group for hydrogenation of carbon
dioxide and bicarbonate, they endeavoured to selectively reduce
the model system of cinnamaldehyde. They quickly identified
the need of an acidic cocatalyst and found that cinnamaldehyde
can be reduced selectively without reducing the olefin. A solvent
screen identified isopropyl alcohol as the optimum solvent, as
lower-chain alcohols lead predominately to formation of acetals.
High temperatures are required, the optimum being 140 °C, at
which temperature catalyst loading can be reduced to 0.05 mol %.
However, for practicality temperatures of 120 °C were chosen
for additional optimization. The optimum reaction conditions are
0.2 to 0.4 mol % [FeF(L)[BF4], 20 bar H2, 120 °C, trifluoroacetic
acid (2 mol %) in isopropyl alcohol. These conditions were
demonstrated on a number of conjugated aldehyde systems and
showed high functional group tolerance providing the allylic
alcohols in >95% yield in most cases. Additionally, a very nice
mechanistic investigation was conducted and reported in detail
(Chem. Eur. J. 2013, 19, 7701−7707).
Junge et al. published an iron-catalyzed reduction of carboxylic
ester to alcohols. After a brief screen of iron and ligand options,
an ideal combination was realized that used 5 mol %
Fe(stearate)2 with 10 mol % 1,2-diaminoethane. The reductant,
polymethylhydrosiloxane (PMHS) was used in 3.0 equiv in
toluene at 100 °C. There was no mention of modifying the
solvent for this transformation. Using these optimized conditions,
the reaction produced moderate and variable yields of the alcohol
products, and showed poor tolerance for other reducible
functionalities. Keto, nitro, and amide groups were fully reduced
under the reaction conditions, while the ester remained largely
intact. Nonetheless, the number of compatible functionalities is
H dx.doi.org/10.1021/op500167y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Green Chemistry Highlights
sufficient to warrant strong consideration of this iron-catalyzed
alternative of a very common transformation (Eur. J. Org. Chem.
2013, 2061−2065).
Another publication focussing on reduction of carboxylic
esters and amides was reported by Fernández-Salas et al. In this
paper, the reduction of esters to alcohols was first approached
using silane-mediated reduction, catalyzed with potassium
hydroxide. After a screen of both silane and base catalyst,
conditions for the reduction of methyl benzoate were identified.
Using 1.1 equiv of phenylsilane with 4 mol % potassium
hydroxide under solvent-free conditions at room temperature
reduction reactions were complete within 1 h. A variety of esters
were reduced under these conditions, some required 60 °C to
achieve complete reduction, and some required the use of a small
amount of THF. Additional solvents were not screened, as the
authors appeared to prefer solvent-free conditions for this
transformation. When applied to amides, these conditions
provided the amines in high yield, though longer reaction times
were required. Again, heating or the use of THF was required in
certain cases. Primary and secondary amides returned only
starting materials; thus, this methodology is currently limited only
to tertiary amides (Chem. Commun. 2013, 49, 9758−9760).
10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC
DISPLACEMENT
Two groups have published studies into the N-alkylation of
heterocyclic amines with alcohols, in particular various benzazoles,
a common motif in pharmacophores. Bala et al. report on the
effectiveness of an iron catalyst for the transformation. Fe(II)-
phthalocyanine (FePc), an inexpensive catalyst the group has
developed for other chemistries, was found to provide good yield
(92%) in a model reaction of 2-aminobenzothiazole with benzyl
alcohol in toluene with sodium tert-butoxide at 100 °C; the
reaction did not proceed in the absence of catalyst. This protocol
provides moderate to very good yields with a wide array of
variously substituted heterocycles as well as providing various
benzazoles via ring closures of ortho-substituted anilines reacting
with alcohols and 2 equiv base at 120 °C. The typical hydrogen-
transfer mechanism of alcohol oxidation, imine coupling, and
reduction was confirmed by intermediate trapping with modified
reaction conditions (Green Chem 2013, 15, 1687−1693).
Organic Process Research & Development
In contrast, Donthiri et al. describe a metal-free N-alkylation
of 2-amino-substituted benzothiazoles, thiazoles, pyridine,
pyrazine, and pyrimidine with benzyl alcohols. The reaction
is conducted in toluene at 120 °C with 20 mol % sodium
hydroxide as catalyst. The reaction does not proceed in DMF,
DMSO, glycerol, or water, whilst chlorobenzene gives a lower
yield in the model alkylation of 2-aminobenzothiazole with
4-chlorobenzyl alcohol. Weaker bases (Na2CO3, K2CO3) and
lower temperatures (e.g., 100 °C) give lower yields, whereas
KOH, NaOtBu, and KOtBu are good (yield >85%), but not as
effective as NaOH. The yield of the reaction is independent
of electron-donating or -withdrawing substituents in either
the benzyl alcohol or 2-aminobenzothiazole with isolated yields
in the range 80−96%. N-benzyl 2-aminothiazole is obtained
in 96% isolated yield, comparable to Bala et al. at a higher
temperature without catalyst. The reaction only proceeds with
benzyl alcohols and pyridinemethanol (J. Org. Chem. 2013, 78,
6775−6781).
The authors in both publications present studies to support
in situ oxidation of the benzylalcohol to the corresponding
benzaldehyde as the first stage of the mechanism, facilitated by
FePc in the first paper and oxygen in the second. These
findings are consistent with the literature and may account for
the differences in reactivity highlighted here.
Heterogeneous catalysts are attractive for their ease of
separation and potential for reuse; however, they can require
extended reaction times at high temperature. Wang et al. have
developed an N-heterocyclic carbene−iridium complex sup-
ported on a mesoporus silica (SBA-15) which was successfully
used to catalyse the N-alkylation of anilines, benzylamine,
cyclohexylamine, and 2-aminopyrimidine and the β-alkylation
of 2° alcohols with benzyl alcohols (hexylalcohol was used in
one example of each transformation). The heterogeneous
catalyst was found to give a superior yield to the corresponding
homogeneous analogue in both transformations. The substrates
were mixed with the catalyst (1.5 mol % Ir), base and heated in
toluene at 110 °C. N-Alkylation reactions were run for 48 h
with NaHCO3 (0.5 equiv) and β-alkylation reactions 24 h with
KOH (1 equiv). The catalyst could be recovered and reused
8 times for β-alkylation and 12 times for amine alkylation. The
authors argue that the SBA-15 support plays an active role in
the reactions by providing a water sink (Adv. Synth. Catal. 2013,
355, 1117−1125).
I dx.doi.org/10.1021/op500167y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Green Chemistry Highlights
Shimizu et al. prepared heterogeneous nickel nanoparticles
supported on θ-alumina for the N-alkylation of anilines and
some primary and secondary amines with a range of alcohols.
Reactions were conducted base free using 1 mol % of catalyst
(5 wt % Ni on θ-alumina) in o-xylene at 144 °C, with 33 h−1
turnover frequency, comparing favorably to other heteroge-
neous systems. Two mol % catalyst was used for the reaction of
aliphatic amines and alcohols. The catalyst was prepared by
reduction of supported nickel oxide under a flow of hydrogen
at 500 °C prior to use. The catalyst was readily separated from
the reaction mixture by centrifugation and could be reused at
least 3 times after regeneration under the reducing conditions.
Mechanistic studies support the hydrogen-borrowing mecha-
nism, and catalyst characterization studies led the authors to
conclude that the metal/support interface is probably the active
site of the catalyst (ACS Catal. 2013, 3, 998−1005).
Continuing the heterogeneous catalyst theme, Yamada et al.
report the use of polyspiroborate iridium catalysts for the
alkylation of amines and ammonia in water. The insoluble
polymeric catalysts were prepared by treating a soluble linear
catecholborate polymer with an iridium species in a mixture of
DME−acetonitrile. Spectroscopic analysis of the resulting
insoluble product shows a material composed of anionic spirobo-
rate polymer with dicationic Ir2+, the iridium acting as a cross-
linker in the polymer. The catalyst (1 mol % Ir) was used for the
alkylation of anilines, benzylamine, dibenzylamine, morpholine,
and 4-hydroxymethylpiperidine with benzyl alcohols in water at
100−150 °C for 24 h. Tribenzylamines could be prepared in
57−95% yield by heating aqueous ammonia with benzyl alcohol
and the catalyst in pH 4 buffer at 150 °C in a microwave reactor
for 24 h; ethyl acetate was used to extract the product during the
work-up. The catalyst was removed by decantation and reused
three times (Synthesis 2013, 45, 2093−2100).
Putra et al. have combined two hydrogen-transfer reactions
for the enantioselective preparation of β-aminoalcohols from
racemic diols. Treatment of excess 1-phenyl-1,2-ethanediol with
secondary amines in the presence of [RuCl2(p-cymene)]2 and
(S,R-Josiphos) for 24 h in toluene at 100 °C affords the amino
alcohol in good to high yield (99% by 1H NMR, 87% isolated
in 1 example) with moderate ee (up to 77%). Mechanistic
studies show that the diol is oxidised to the corresponding keto-
aldehyde which undergoes reductive amination of the aldehyde
followed by asymmetric hydrogenation of the ketone (Eur. J.
Org. Chem. 2013, 6146−6151) (Scheme 1).
Three publications describe the use of CO2 as a C1 building
block for amine methylation. Jacquet et al. utilise phenylsilane
(2 equiv) and a mixture of an N-heterocyclic carbene and
zinc chloride (5 mol %) in THF for N-methylation of
Organic Process Research & Development
Scheme 1
N-methylanilines. N,N-dimethylaniline was obtained in 95%
yield after 20 h at 100 °C, under 1 bar CO2. The influence of
electron-donating and -withdrawing substituents and their sub-
stitution position were explored, and the reaction was extended
to 1° amines and anilines with variable results; treatment of
aniline for 72 h afforded a mixture of N,N-dimethylaniline (79%)
and N-methyl-N-phenylformamide (21%) (Chem. Sci 2013, 4,
2127−2131). Li et al. have found a ruthenium-based catalyst
system for use with phenylsilane (4 equiv) in toluene at 100 °C,
under 30 bar CO2 for the N-methylation of a wider range of 2°
amines; there are 22 examples with isolated yields ranging from
61−99% (Angew. Chem. Int. Ed. 2013, 52, 9568−9571).
Beydoun et al. use molecular hydrogen (60 bar) as the reductant
in the presence of a ruthenium catalyst in THF at 150 °C, under
20 bar CO2 (Angew. Chem. Int. Ed. 2013, 52, 9554−9557).
There is some overlap of examples with the previous paper and
neither method is superior in all cases. Anilines and primary
amines are dimethylated using both methods. All three groups
present studies that support a formamide intermediate.
11. FRIEDEL−CRAFTS CHEMISTRY
Wang et al. have demonstrated a one-pot synthesis of pyrrolo-
[1,2-a]quinolin-1-ones from the reactions of 5-hydroxy-1-
arylpyrrolidin-2-ones with 1,3-dicarbonyl compounds using
H3PO4/P2O5 or HOAc/H2SO4. The examples utilizing ethyl
acetoacetate and acetylacetone were generally high yielding;
however, when ethyl benzoyl acetate was employed, lower yields
were obtained. Presumably this is due to the steric hindrance of
final cyclization. The substituents on the phenyl ring also have a
J dx.doi.org/10.1021/op500167y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Green Chemistry Highlights
great influence. Not surprisingly, electron-donating groups
enhance the reactivity over substrates bearing electron-with-
drawing groups. The mechanism is presumed to proceed via
addition of the 1,3-dicarbonyl compound to an N-acyliminium
ion intermediate (from the initial dehydration of the hydroxyl
group) followed by ring closure via Friedel−Crafts alkylation
(J. Heterocycl. Chem. 2013, 50, 501−505).
12. CHEMISTRY IN WATER
Chou and Raines describe the conversion of azides into diazo
compounds in water. By the use of water as solvent the
applicability of this conversion in chemical biology can become
of potential interest. The process is illustrated for the synthesis
of various diazoacetic acid esters and amides, and a wide range
of functional groups are tolerated.
The authors report the design and optimization of a water-
soluble activated phosphinoester used in stoichiometric
quantities to mediate the azide to diazo conversion in a phos-
phate buffer solution of pH 7. Especially, the reaction almost
exclusively produced the diazo compound without side-product
formation of Staudinger ligation if the conjugated acid of the
leaving group in the phosphinoester has a pKa < 7 (J. Am.
Chem. Soc. 2013, 135, 14936−14939).
By the developments in modern click chemistry the 1,2,3-
triazole group has become a privileged scaffold in many bioactive
molecules. An alternative preparation of these triazoles is by an
organocatalyzed 1,3-dipolar cycloaddition reaction of ketones
and azides. However, the reported reactions are restricted to the
use of organic solvents. Yeung et al. now describe the use of
water as solvent for this 1,3-dipolar cycloaddition using 20 mol %
of proline N,N-dioctylamide as organocatalyst. This reaction in
water at 80 °C is applied to a wide range of ketones and aromatic
azides (Green Chem. 2013, 15, 2384−2388).
A new method for aroylation with CO and aryl iodides via
ruthenium-catalyzed C−H activation of (hetero)arenes bearing
Organic Process Research & Development
ortho-directing groups is described by Beller and co-workers.
Remarkably, the reactivity of this carbonylative C−C coupling
was dramatically increased by changing the organic solvent to
water. The best reaction conditions identified are 5 mol % of
RuCl2(cod) catalyst and 0.2 equiv of KOAc as additive, using
NaHCO3 (2 equiv) as base and 30 bar CO at 120 °C for 20 h.
Pyridine-2-yl, N-pyrazole, and pyrimidine-2-yl have been used
as ortho-directing groups (Angew. Chem. Int. Ed. 2013, 52,
6293−6297).
The iron(III)-catalyzed direct nucleophilic substitution of
allylic (benzylic) alcohols with a wide range of nucleophiles has
been described by Trillo et al. Although the application of
FeCl3 Lewis acid-catalyzed processes in water have been known
for some time (e.g. in Mukiyama aldol reactions) examples of
direct substitution of free allylic alcohols in water are rare.
Various sulfonamides and anilines, as well as benzyl carbamate,
benzamide, benzotriazole, and TMSN3 can be used as nitrogen
nucleophiles, but no conversion was observed with tert-butyl
carbamate and basic amines (benzylamine, butylamine,
ammonia). Also carbon nucleophiles such as allyltrimethylsi-
lane, TMSCN, anisole, indole, or diethyl malonate can be used.
Use of FeO(OH)·2H2O instead of FeCl3 as the catalyst worked
equally well or even slightly better for less acidic sulfonamides,
anilines, and indole. The low toxicity of FeCl3, the use of water,
and the lack of leaving group activation makes this conversion
of special interest (ChemCatChem 2013, 5, 1538−1542).
In recent years various successful examples of sp2 C−H bond
activation in water and the application in a variety of catalytic
cross-coupling reactions have been described in the literature.
These cross-coupling reactions and the role of water as a
solvent have been reviewed in a recent paper by Li and Dixneuf
(Chem. Soc. Rev. 2013, 42, 5744−5767).
Tomasek and Schatz review recent developments of olefin
metathesis in aqueous media. The two main strategies are
discussed: design and application of water-soluble catalysts and
the use of commercial catalysts under heterogeneous micellar
conditions (Green Chem. 2013, 15, 2317−2338).
13. CONTINUOUS PROCESSING AND PROCESS
INTENSIFICATION
Yoshida et al. published a featured article on the use of micro
reactors to enable flash chemistry (i.e., chemistry that is unsuit-
able for batch/semibatch processing) involving extremely fast
reactions (<1 s) and highly reactive and unstable inter-
mediates. The authors detail the approaches used supported
with various examples of successful application of active in situ
catalyst generation and multistep consecutive lithiation reac-
tions for protecting-group-free synthesis (Chem. Commun 2013,
49, 9896−9904).
K dx.doi.org/10.1021/op500167y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Green Chemistry Highlights
In another interesting article by Grego et al., details of a
catalytic fixed bed continuous process for the synthesis of
methyl phenylcarbamate by carbamoylation of aniline by dimethyl
carbonate in the presence of zinc carbonate catalyst has been
reported. Detailed studies on parametric effects influencing this
phosgene-free process showed high conversions (∼98% at
200 °C) and selectivity (97%) without any significant catalyst
deactivation even after 180 h despite a reaction stoppage and
restart in between (Org. Process Res. Dev. 2013, 17, 679−683).
Pedersen et al. made use of a setup where a continuous
stirred tank reactor (CSTR) and static mixer reactor were
connected in series to overcome challenges associated with
impurity formation and handling of suspended solids in plug
flow reactors for the Grignard alkylation reaction of 2-chloro-
thioxanthen-9-one with allylmagnesium chloride. The CSTR
was used to generate and retain the solid phase, whereas an
outward line fitted with a filter was used to transfer the
homogeneous liquid phase into plug flow static mixer reactor
to achieve higher conversions of the unreacted ketone (Org.
Process Res. Dev. 2013, 17, 1142−1148).
Lehmann et al. carried out an inverse-electron-demand
Kondrat’eva reaction to generate cycloalka[c]pyridines from
unactivated oxazoles and cycloalkenes in a continuous tubular
reactor under conditions of elevated temperature and pressure.
Continuous flow reactor characteristics offer much better
control and efficiency over batch reactors under the required
extreme operating conditions (230 °C and 750 psi), and the
process offers easy access to annulated pyridines (Org. Lett.
2013, 15, 3550−3553).
14. GENERAL GREEN CHEMISTRY
Adams et al. from GSK have published an article on GSK’s
reagent guide which has the objective of embedding sustainabi-
lity into reagent selection. The assessment includes a combined
environmental score, heath score, and safety score, a chemistry
score which takes into account factors such as work-up, stoi-
chiometry, and atom efficiency. Three of the reagent guides
are published in the paper with a further 12 shared in the
Supporting Information. The format is impactful and easy to
use (Green Chem 2013, 15, 1542−1549).
Leahy et al., have published an article proposing seven key
elements of an effective Green Chemistry program with examples
from several pharmaceutical companies. The seven key elements
are (i) empowered Green Chemistry teams with management
support, (ii) metrics and targets, (iii) resources and tools, (iv)
Organic Process Research & Development Green Chemistry Highlights

education, (v) awareness and recognition, (vi) investments in

green technology, and (viii) external collaboration (Org. Process
Res. Dev. 2013, 17, 1099−1109).
Rakeshwar Bandichhor
Dr. Reddy’s Laboratories Ltd., Innovation Plaza, IPDO,
Bachupally, Hyderabad, Andhra Pradesh, India 500072
Apurba Bhattacharya
Dr. Reddy’s Laboratories Ltd., Innovation Plaza, IPDO,
Bachupally, Hyderabad, Andhra Pradesh, India 500072
Louis Diorazio
AstraZeneca, Macclesfield SK10 2NA, U.K.
Peter Dunn
Pfizer Global Research and Development, Ramsgate Road,
Sandwich, Kent, CT13 9NJ U. K.
Kenneth Fraunhoffer
Bristol-Myers Squibb, Co., One Squibb Drive, New
Brunswick, New Jersey 08903, United States
Fabrice Gallou
NovartisPharma AG, Forum 1, Novartis Campus, 4056
Basel, Switzerland
John Hayler*
GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY
U.K.
Matthew Hickey*
Bristol-Myers Squibb, Co., One Squibb Drive, New
Brunswick, New Jersey 08903, United States
Bill Hinkley
GlaxoSmithKline, Research Triangle Park, North Carolina
27709, United States
David Hughes
Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey
07065, United States
Luke Humphreys
GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY
U.K.
Bernard Kaptein
DSM Innovative Synthesis BV, P.O. Box 18, 6160
Maryland Geleen, The Netherlands
Suju Mathew
Pfizer Global Research and Development, Ramsgate Road,
Sandwich, Kent, CT13 9NJ U. K.
Lynnette Oh
GlaxoSmithKline, King of Prussia, Pennsylvania 19406,
United States
Paul Richardson
Pfizer Global Research and Development, 10578 Science
Center Drive, La Jolla, California 92121, United States
Timothy White
Eli Lilly, Indianapolis, Indiana United States
Stijn Wuyts
Janssen Pharmaceutical Companies of Johnson and
Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium

■ AUTHOR INFORMATION
Corresponding Authors
*E-mail: John.Hayler@gsk.com.
*E-mail: Matthew.Hickey@bms.com.

L dx.doi.org/10.1021/op500167y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX